19-Hydroxy-19-methyl-4,5-didehydro-PGI1 compounds

ABSTRACT

The present invention provides novel 19-hydroxy-19-methyl-4,5-didehydro-PGI 1  compounds which are useful for pharmacological purposes, e.g., anti-asthmatic indications.

CROSS REFERENCE TO RELATED APPLICATION

The present invention is a divisional application of U.S. Ser. No. 054,720, filed July 5, 1979 now U.S. Pat. No. 4,225,507.

BACKGROUND OF THE INVENTION

The present invention provides novel prostacyclin analogs. Particularly, the present invention relates to prostacyclin analogs substituted at the C-19 position by hydroxy.

Particularly, the present invention relates to 19-hydroxy-19-methyl-5,6-didehydro-PGI₁ compounds. The novel prostacyclin analogs are useful for pharmacological purposes, e.g., as anti-asthmatic agents. The preparation and use of these compounds is incorporated here by reference from U.S. Pat. No. 4,225,507.

PRIOR ART

For background on prostacyclin, see for example R. A. Johnson, et al., Prostaglandins 12, 915-928 (1976) and R. A. Johnson, et al., J. Am. Chem. Soc. 100, 7690-7704 (1978), and, as to pharmacological activity, the references cited therein. For analogs of prostacyclin, see, for example, J. Fried, et al., Proc. Natl. Acad. Sci. U.S.A. 74, 2199-2203, K. C. Nicolaou, et al., J.C.S. Chem. Comm. 1977, 331-332, N. A. Nelson, J. Am. Chem. Soc. 99, 7362-7363 (1977), and K. Kojima, et al., Tetra. Letters, 1978, (1977), and K. Kojima, et al., Tetra. Letters, 1978, 3743-3746. Regarding the nomenclature for analogs of PGI₂, see R. A. Johnson, et al., Prostaglandins 15, 737-740 (1978).

SUMMARY OF THE INVENTION

The present invention particularly provides a prostacyclin-type compound of the formula ##STR1## wherein A₁ is --O-- (oxa) and E₁ is --CH₂ --; wherein L₂ is

(1) --(CH₂)_(j) --, wherein j is one to 4, inclusive,

(2) --(CH₂)_(q) --CF₂ --, wherein q is one, 2, or 3; or

(3) --CH═CH--;

wherein Q is oxo, α-H:β-H, α-OH:β-R₄, or α-R₄ :β-OH,

wherein R₄ is hydrogen or alkyl of one to 4 carbon atoms, inclusive,

wherein R₁ is

(1) --COOR₃,

(2) --CH₂ OH,

(3) --CH₂ N(R₇)(R₈),

(4) --CO--N(R₇)(R₈),

(5) --CO--NH--SO₂ --R₁₅, or

(6) tetrazolyl,

wherein R₃ is

(a) hydrogen,

(b) alkyl of one to 12 carbon atoms, inclusive,

(c) cycloalkyl of 3 to 10 carbon atoms, inclusive,

(d) aralkyl of 7 to 12 carbon atoms, inclusive,

(e) phenyl,

(f) phenyl substituted with one, 2, or 3 chloro or alkyl groups of one to 3 carbon atoms, inclusive,

(g) --(p--Ph)--CO--CH₃,

(h) --(p--Ph)--NH--CO--(p--Ph)--NH--CO--CH₃,

(i) --(p--Ph)--NH--CO--(Ph),

(j) --(p--Ph)--NH--CO--CH₃,

(k) --(p--Ph)--NH--CO--NH₂,

(l) --(p--Ph)--CH═N--NH--CO--NH₂,

(m) β-naphthyl,

(n) --CH₂ --CO--R₁₆,

wherein --(p--Ph)-- is para-phenylene and --(Ph) is phenyl;

wherein R₁₆ is phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl, or 2-naphthyl, or

(o) a pharmacologically acceptable cation; wherein R₇ and R₈ are hydrogen, alkyl of one to 12 carbon atoms, inclusive, benzyl, or phenyl, being the same or different, and wherein R₁₅ is hydrogen, alkyl of one to 12 carbon atoms, inclusive, phenyl, phenyl-substituted with one, 2, or 3 chloro or alkyl groups of one to 3 carbon atoms, inclusive, or phenyl substituted with hydroxycarbonyl or alkoxycarbonyl of one to 4 carbon atoms, inclusive, wherein R₂ is hydrogen, hydroxyl, or hydroxymethyl, wherein R₅ and R₆ are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same or different, with the proviso that one of R₅ and R₆ is fluoro only when the other is hydrogen or fluoro, and

wherein X is

(1) trans--CH═CH--,

(2) cis--CH═CH--,

(3) --C.tbd.C--, or

(4) --CH₂ CH₂ --.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention particularly relates to the following compounds:

(4E)-2-Decarboxy-2-hydroxymethyl-9-deoxy-6ξ,9α-epoxy-Δ⁴ -19-hydroxy-19-methyl-PGF₁, and

(4E)-2-Decarboxy-2-hydroxymethyl-9-deoxy-6ξ,9α-epoxy-Δ⁴ -16,16-difluoro-19-hydroxy-19-methyl-PGF₁. 

What is claimed is:
 1. A prostacyclin-type compound of the formula ##STR2## wherein A₁ is --O-- (oxa) and E₁ is --CH₂ --; wherein L₂ is(1) --(CH₂)_(j) --, wherein j is one to 4, inclusive, (2) --(CH₂)_(q) --CF₂ --, wherein q is one, 2, or 3; or (3) --CH═CH--;wherein Q is oxo, α-H:β-H, α-OH:β-R₄, or α-R₄ :β-OH, wherein R₄ is hydrogen or alkyl of one to 4 carbon atoms, inclusive, wherein R₁ is (1) --COOR₃, (2) --CH₂ OH, (3) --CH₂ N(R₇)(R₈), (4) --CO--N(R₇)(R₈), (5) --CO--NH--SO₂ --R₁₅, or (6) tetrazolyl,wherein R₃ is (a) hydrogen, (b) alkyl of one to 12 carbon atoms, inclusive, (c) cycloalkyl of 3 to 10 carbon atoms, inclusive, (d) aralkyl of 7 to 12 carbon atoms, inclusive, (e) phenyl, (f) phenyl substituted with one, 2, or 3 chloro or alkyl groups of one to 3 carbon atoms, inclusive; (g) --(p--Ph)--CO--CH₃, (h) --(p--Ph)--NH--CO--(p--Ph)--NH--CO--CH₃, (i) --(p--Ph)--NH--CO--(Ph), (j) --(p--Ph)--NH--CO--CH₃, (k) --(p--Ph)--NH--CO--NH₂, (l) --(p--Ph)--CH═N--NH--CO--NH₂, (m) β-naphthyl, (n) --CH₂ --CO--R₁₆,wherein --(p--Ph)-- is para-phenylene and --(Ph) is phenyl; wherein R₁₆ is phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl, p-nbenzamidophenyl, or 2-naphthyl, or(o) a pharmacologically acceptable cation; wherein R₇ and R₈ are hydrogen, alkyl of one to 12 carbon atoms, inclusive, benzyl, or phenyl, being the same or different, and wherein R₁₅ is hydrogen, alkyl of one to 12 carbon atoms, inclusive, phenyl, phenyl-substituted with one, 2, or 3 chloro or alkyl groups of one to 3 carbon atoms, inclusive, or phenyl substituted with hydroxycarbonyl or alkoxycarbonyl of one to 4 carbon atoms, inclusive, wherein R₂ is hydrogen, hydroxyl, or hydroxymethyl, wherein R₅ and R₆ are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same or different, with the proviso that one of R₅ and R₆ L is fluoro only when the other is hydrogen or fluoro, and wherein X is(1) trans-CH═CH--, (2) cis-CH═CH--, (3)--C.tbd.C--, or (4) --CH₂ CH₂ --.
 2. A compound according to claim 1, wherein R₁ is --CH₂ OH.
 3. A compound according to claim 2, wherein L₂ is --(CH₂)₂, Q is α-OH:β-H, R₂ is hydroxyl, and X is trans-CH═CH--.
 4. (4E)-2-Decarboxy-2-hydroxymethyl-9-deoxy-6ξ,9α-epoxy-Δ.sup.4 -19-hydroxy-19-methyl-PGF₁, a compound according to claim
 3. 5. (4E)-2-Decarboxy-2-hydroxymethyl-9-deoxy-6ξ,9α-epoxy-.DELTA.⁴ -16,16-difluoro-19-hydroxy-19-methyl-PGF₁, a compound according to claim
 3. 